A simple and convenient synthesis of β-amino alcohol chiral auxiliaries based on limonene oxide

Article abstract of DOI:10.1016/S0040-4039(01)01135-2

A series of chiral β-amino alcohols was prepared by the reaction of secondary amines with a 1:1 mixture of cis- and trans-limonene oxide in the presence of water as a catalyst. The β-amino alcohol obtained was derived from the trans-limonene oxide, and the unreacted cis-limonene oxide was recovered from the reaction mixture. The β-amino alcohols are useful chiral auxiliaries for the addition of diethylzinc to benzaldehyde.

Full text of DOI:10.1016/S0040-4039(01)01135-2

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 42 (2001) 5805–5807
A simple and convenient synthesis of b-amino alcohol chiral
auxiliaries based on limonene oxide
Will Chrisman,a Jason N. Camara,a Kim Marcellini,a Bakthan Singaram,a,* Christian T. Goralski,b
Dennis L. Hasha,b Philip R. Rudolf,b Lawrence W. Nicholsonb and Karen K. Borodychukb
aDepartment of Chemistry and Biochemistry, University of California, Santa Cruz, CA 95064, USA
bContract Manufacturing Services, The Dow Chemical Company, 1710 Building, Midland, MI 48674, USA
Received 21 May 2001; accepted 6 June 2001
Abstract—A series of chiral b-amino alcohols was prepared by the reaction of secondary amines with a 1:1 mixture of cis- and
trans-limonene oxide in the presence of water as a catalyst. The b-amino alcohol obtained was derived from the trans-limonene
oxide, and the unreacted cis-limonene oxide was recovered from the reaction mixture. The b-amino alcohols are useful chiral
auxiliaries for the addition of diethylzinc to benzaldehyde. © 2001 Elsevier Science Ltd. All rights reserved.
O
O
OH
O
H
H2O
HNR1R2
NR1R2
+
+
+
Reflux
1
2
3
2
1:1 Mixture
The literature abounds with examples of the use of
b-amino alcohols as chiral auxiliaries in a variety of
synthetic organic reactions.1 In many instances, these
materials are prepared by lengthy syntheses in which
one-step involves ‘classical resolution’ or another sepa-
ration technique to obtain one pure enantiomer. Sev-
eral years ago, we recognized that one way to avoid
enantiomer separation was to start the b-amino alcohol
synthesis with a naturally occurring, readily available
chiral material, such as a terpene. We demonstrated this
concept with the synthesis of (1R,2S,3S,5R)-2-(dialkyl-
amino)-6,6-dimethylbicyclo[3.1.1]heptan-3-ols via the
hydroboration/oxidation of the corresponding enam-
ines of (R)-(+)-nopinone.2 The concept was further
demonstrated by Masui and Shioiri who prepared
(1S,2S,3R,5S)- and (1R,2R,3S,5R)-3-amino-2-hydroxy-
pinane and demonstrated the utility of their oxaz-
aborolidine derivatives in the asymmetric reduction of
prochiral ketones.3 Most recently, Nugent and cowork-
ers have similarly taken advantage of the chirality
present in (+)-3-carene to prepare a highly effective
chiral auxiliary for the addition of lithium cyclopropyl-
acetylide to an unprotected N-acylketimine in high
enantiomeric excess.4 In furthering our investigation of
terpene based chiral auxiliaries, we now describe the
synthesis of a series of new b-amino alcohol chiral
auxiliaries from the reaction of (R)-(+)- or (S)-(−)-
limonene oxide with secondary amines.
Obtaining b-amino alcohols via the opening of epoxides
with amines is an approach that has been utilized as
early as 1923.5 (R)-(+)-Limonene oxide is a readily
available and inexpensive starting material due to the
natural abundance of its precursor, (R)-(+)-limonene.6
However, epoxidation of the endocyclic double bond
creates a 1:1 mixture of trans-limonene oxide (1) and
cis-limonene oxide (2) which is difficult to separate.7
Pure cis-(R)-(+)-limonene oxide (2) has been prepared
from the corresponding diol.8 Pure cis-(R)-(+)-limonene
oxide (2) and trans-(R)-(+)-limonene oxide (1) have
* Corresponding author. Tel.: (831)459-3154; fax: (831)459-2935;
e-mail: singaram@chemistry.ucsc.edu
0040-4039/01/$ - see front matter © 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(01)01135-2

5806
W. Chrisman et al. / Tetrahedron Letters 42 (2001) 5805–5807
OH
O
O
H
H2O
NR1R2
HNR1R2
+
+
Reflux
1
2
3
1:1 Mixture
HN
HN
O
HNR1R2 =
HN
,
NCOCH2CH3
,
HN
O
HN
S
HN
NCH3
,
,
,
,
,
HN
HN
CH3
HN
HN
CO2CH2CH3
,
CH3 HN
CH2C6H5 HN
,
,
,
CH2
Scheme 1.
transition states.12 Attack of secondary amine at C-2 of
1 proceeds through a favorable ‘chair-like’ transition
state, while attack at C-2 of 2 cannot occur due to the
development of an energetically unfavorable ‘boat-like’
transition state.
been prepared by Hofmann degradation of the two
isomeric amino alcohols obtained from the reaction of
the mixture of 1 and 2 with aqueous dimethylamine.9,10
The reaction of ammonia and lower alkylamines with a
1:1 mixture of 1 and 2 has been reported to give the
corresponding mixture of amino alcohol diastereomers
which have been separated by selective crystallization
of acid salts.10,11 Consequently, limonene oxide has not
been used as a precursor for the synthesis of b-amino
alcohol chiral auxiliaries.
Encouraged by these results, we reacted the series of
secondary amines with the 1:1 mixture of 1 and 2 in the
presence of water at reflux to give a corresponding
series of b-amino alcohols 3 derived from the reaction
of 1 (Scheme 1).†
We now report here conditions which permit the
diastereoselective preparation of b-amino alcohols from
the 1:1 mixture of 1 and 2, and the use of these new
b-amino alcohols as chiral auxiliaries in the addition of
diethylzinc to benzaldehyde.
The cis-limonene oxide (2) was recovered from the
reaction mixture by simple distillation, leaving the
crude b-amino alcohol. The crude b-amino alcohol was
purified by isolation of the oxalate salt, followed by
treatment with potassium hydroxide to give the free
We selected a series of secondary amines for our study.
The initial reaction was run with morpholine. The
reaction was conducted neat with approximately three
equivalents of morpholine to the 1:1 mixture of 1 and 2,
and the progress of the reaction was monitored by
capillary GC. Surprisingly, even after 7 days at 110°C,
only 11% reaction occurred. Addition of p-toluenesul-
fonic acid (PTSA) did not improve the rate of the
reaction.
O
+ (CH3CH2)2Zn
H
OH
H
NR1R2
Toluene
0 oC
We found, however, that water was an excellent cata-
lyst for the reaction. The capillary GC analyses of the
reaction of morpholine with the 1:1 mixture of 1 and 2
in the presence of a catalytic amount of water indicated
that one diastereomer was reacting much faster than
the other. Spiking a reaction sample with authentic
cis-(R)-(+)-limonene oxide (2) confirmed that 1 was
reacting with morpholine much faster than 2. We thus
found that it was possible to stop the reaction after
approximately 12 hours and isolate diastereomerically
OH
H
CCH2CH3
4
Scheme 2.
† The reaction sequence shown in Scheme 1 shows (R)-(+)-limonene
oxide as the starting material to give the corresponding (1S,2S,4R)-
2-dialkylamino-1-methyl-4-(1-methylethenyl)cyclohexanol (3). Iden-
tical reactions were carried out with (S)-(−)-limonene oxide to give
the corresponding (1R,2R,4S)-2-dialkylamino-1-methyl-4-(1-methyl-
ethenyl)cyclohexanol.
pure b-amino alcohol
3 and unreacted 2. The
diastereoselectivity observed in the reaction between a
1:1 mix of 1 and 2 with secondary amines can be
explained in terms of conformational differences in the

W. Chrisman et al. / Tetrahedron Letters 42 (2001) 5805–5807
5807
Table 1. Limonene oxide-derived b-amino alcohols as chiral auxiliaries for the addition of diethylzinc to benzaldehyde
Entry
b-amino alcohol
% 4
% ee
[h]2D5
1
2
3
4
(1S,2S,4R)-1-methyl-4-(1-methylethenyl)-2-(4-morpholinyl)cyclohexanol
(1S,2S,4R)-1-methyl-4-(1-methylethenyl)-2-(1-pyrrolidinyl)cyclohexanol
(1S,2S,4R)-1-methyl-4-(1-methylethenyl)-2-(1-piperidinyl)cyclohexanol
(1S,2S,4R)-2-(benzylmethylamino)-1-methyl-4-(1-methylethenyl)cyclohexanol
98
80
80
80
78
85
82
85
37.5
43.0
39.4
43.0
base, which was subsequently distilled or recrystallized.‡
Four of the b-amino alcohols derived from (R)-(+)-
limonene oxide were utilized as chiral auxiliaries in the
addition of diethylzinc to benzaldehyde to produce
(R)-1-phenyl-1-propanol (4) with 78–85% ee (Scheme 2,
Table 1).§
alcohol chiral auxiliaries in both enantiomeric forms
from readily available and inexpensive (R)-(+)-
limonene and (S)-(−)-limonene, via their epoxides, and
a variety of secondary amines. The utility of these new
b-amino alcohols as chiral auxiliaries is currently under
investigation.
In summary, we have demonstrated a simple and con-
venient synthesis of a new family of chiral b-amino
Acknowledgements
We thank Roche Biosciences for a fellowship to Jason
N. Camara.
‡ General procedure: (−)-(1R,2R,4S)-1-Methyl-4-(1-methylethenyl)-2-
(4-morpholinyl)cyclohexanol. A 250 mL, single-neck flask equipped
with a magnetic stirring bar and a reflux condenser fitted with a
nitrogen bubbler was charged with 54.78 g (0.360 mol) of (S)-(−)-
limonene oxide, 90 mL of morpholine, and 10 mL of deionized
water. The mixture was heated to reflux and held there for 68.5 h.
The reaction mixture was cooled to room temperature. The excess
morpholine and limonene oxide were distilled off at reduced pres-
sure to give 64.38 g of crude amino alcohol as a dark orange,
viscous oil. The crude amino alcohol was dissolved in 90 mL of
References
1. (a) Asymmetric Catalysis in Organic Synthesis; Noyori,
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methanol. To the stirred solution, a solution of 33.00 g (0.366 mol)
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drum quantities.
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of oxalic acid in 300 mL of methanol was slowly added. A heavy
slurry of white solid formed immediately. The slurry was cooled
with an ice bath and stirred for 0.5 h. The solid was isolated by
filtration, air dried, washed with 75 mL of cold (ice bath) methanol,
and vacuum dried at 60°C to give 54.55 g of the oxalate salt of (−)-
(1R,2R,4S)-1-methyl-4-(1-methylethenyl)-2-(4-morpholinyl)cyclo-
hexanol as a white solid, mp 206–207°C (dec.). The oxalate salt
(53.55 g) was transferred to a separatory funnel and mixed with 600
mL of 1N potassium hydroxide and 200 mL of diethyl ether. The
mixture was shaken and the layers separated. The aqueous layer
was extracted with two 200 mL portions of diethyl ether. The
combined ether fractions were washed with 100 mL of deionized
water. The ether solution was dried over anhydrous magnesium
sulfate. The diethyl ether was removed in vacuo (rotary evaporator)
leaving 35.56 g of (−)-(1R,2R,4S)-1-methyl-4-(1-methylethenyl)-2-
(4-morpholinyl)cyclohexanol as a pale yellow oil. A few seed crys-
tals of (−)-(1R,2R,4S)-1-methyl-4-(1-methylethenyl)-2-(4-morpho-
linyl)cyclohexanol from a previous batch were added, and crystal-
lization began immediately. The oil completely crystallized, and was
broken up with a spatula to give a white solid, mp 43–44°C.
§ General procedure for (R)-1-phenyl-1-propanol (4). To a 25 mL,
round-bottom flask charged with the b-amino alcohol (1 mmol) was
added diethylzinc in toluene (10.0 mL, 10 mmol) under nitrogen.
The solution was stirred for 25 min at room temperature and then
cooled to 0°C. Benzaldehyde (1.0 mL, 10 mmol) was added drop-
wise via syringe, and the reaction mixture was allowed to reach
room temperature while stirring over night. The reaction mixture
turned yellow upon addition of the benzaldehyde, but became
colorless after stirring for 24 h. The reaction was acidified with 12
M hydrochloric acid and extracted with diethyl ether (5×30 mL).
The combined ether extracts were dried and the solvent removed in
vacuo. The resulting oil was distilled under reduced pressure to give
(R)-1-phenyl-1-propanol, bp 47–50°C (1.0 Torr). Optical rotation
(see Table 1) c=1.0 in cyclohexane).
12. Raban, M.; Burch, D. L.; Hortelano, E. R.; Durocher, D.
J. Org. Chem. 1994, 59, 1283–1287.